Ever since the discovery of insulin and its successive use for the treatment of Diabetes the only form of administration used in practice has been subcutaneous or intramuscular injection, generally several times a day. In spite of a rapid technical development, this administration still involves a number of disadvantages, such as pain, risk of infection as well as a possibility of chronic tissue injuries. Consequently, there has always been a wish to administer the insulin non-parenterally, and thus in particular oral, rectal, nasal, as well as ophthalmic administrations have been investigated.
The ophthalmic administration of insulin has been disclosed in the specification of Danish Patent No. 135,268, according to which specification an insulin-containing hydrogel is placed under the eyelid. Thereby an absorption of 5-20% of the amount of insulin administered is obtained over a period of several hours.
The oral administration demands that special protective measures are taken in order to prevent the insulin from being decomposed, before absorption can take place through the intestinal mucosa. This can e.g. be done as stated in the specification of Danish patent application No. 1925/83 and Danish patent application No. 2294/84, according to which enzyme inhibitors are added and an encapsulation in a bile-soluble material may be made. Oral administration only gives an absorption of 1-2% of the amount of insulin administered, cf. Galloway et al., Diabetes 21 (1971), pages 640-648.
Rectal insulin administration is disclosed in e.g. German Published Specification No. 2,641,819, U.S. Pat. No. 4,164,573 and U.S. Pat. No. 4,442,090. In this way of administration the insulin is encapsuled in the form of a suppository in which the presence of an enzyme inhibitor is normally not necessary. Hereby an absorption of the amount of insulin administered of about 5% can be obtained.
In the forms of administration mentioned above use is made in almost all cases of a surface-active additive to increase the absorption rate and efficiency of the insulin through the mucosae. An example of such absorption promoting adjuvants are polyoxy ethylene fatty alcohol ethers and in particular bile acids or salts thereof.
Such additives are particularly effective in nasal administration of insulin, vide GB Patent Specifications No. 1,527,605 and No. 1,554,157, and the technique has been further described by S. Hirai et al., Diabetes 27 (1978), pages 296-299, and G. S. Gordon et al., PNAS 82 (1985), pages 7419-7423. In this form of administration the insulin is administered in solution as drops or better in atomized form to the nasal cavity, whereafter the absorption through the nasal mucosa occurs so rapidly, that the maximum insulin concentration is obtained already after 10 to 30 minutes. This rapidly commencing absorption is of particularly therapeutical importance as the maximum insulin concentration in normal subcutaneous injection of dissolved insulin does not commence until after 30-60 minutes, which may cause problems in a much employed Diabetes therapy, in which injections of rapidly acting insulin are given immediately before the principal meals.
However, in the nasal form of administration an adverse effect on the mucosae due to the added absorption promoting adjuvants has been demonstrated after some time, vide S. Hirai et al., Int. J. Pharm. 9 (1981), pages 173-184.
This problem is said to be solved by the use of certain fusidic acid or cephalosporine derivatives as adjuvants, vide the specification of European patent application No. 128,831. The proportion of insulin absorbed by nasal administration in dissolved and atomized form is said to be up to about 20% in the publications mentioned above.
An embodiment of the nasal administration in which the use of surface-active adjuvants can be avoided is known from European patent application No. 122,036. Said embodiment consists in the administration of the insulin as a powder, whereby use is made of a water-insoluble, but water-absorbing carrier, e.g. crystalline cellulose. Hereby the particles adhere to the nasal mucosa, and moisture is absorbed which has the effect that the insulin attains an intense contact with the mucosa and thereby can be absorbed with a high efficacy.
In all the known insulin preparations for non-parenteral administration a conventional commercially available insulin is used as the basis of the formulation. When such an insulin is dissolved at physiological pH value a concentration-dependent equilibration is established between monomeric, dimeric, hexameric, and polymeric insulin. The degree of self-association can be determined e.g. by ultracentrifugation or by gel filtration methods, vide e.g. R. Valdes Jr. and G. A. Ackers, "Methods in Enzymology", Vol. 61 (Enzyme Structure, part H, edt.: Hirs & Timasheff), Academic Press 1979, pages 125-142. In conventional commercially available preparations of dissolved insulin a very large proportion of the insulin is present as hexamers.
SUMMARY OF THE INVENTION
By the use of insulins or insulin derivatives which in solution in the physiological pH range predominantly are present as monomers in insulin preparations for non-parenteral administration a still more rapid absorption of the insulin activity administered is obtained, as maximum concentration in serum is attained already after 5-10 minutes.